Trigonelline Plus Sufentanil for Postoperative Analgesia After Laparoscopic Hysterectomy: A Randomized Controlled Clinical Trial

Background and Rationale Gynecologic laparoscopic surgery has become the predominant surgical approach for both benign and malignant gynecologic conditions in China and globally. Despite its minimally invasive advantages over open laparotomy - including smaller incisions, reduced blood loss, shorter hospital stays, and faster return to daily activities - postoperative pain remains a clinically significant challenge. Inadequately controlled acute postoperative pain can impair respiratory function, delay ambulation, increase the risk of deep vein thrombosis and pulmonary complications, prolong hospital stay, and contribute to the development of chronic postsurgical pain.

Postoperative nausea and vomiting (PONV) is among the most common and distressing adverse events following gynecologic laparoscopic surgery under general anesthesia. Female sex, laparoscopic surgical technique, and postoperative opioid use are well-established independent risk factors for PONV, with reported incidence rates in this population ranging from 40% to 80% in published literature.

Conventional mu-opioid receptor agonists - including sufentanil, fentanyl, and morphine - remain the cornerstone of postoperative analgesia due to their potent and reliable analgesic efficacy. However, these agents exert their effects through G-protein-mediated signaling as well as through recruitment of beta-arrestin pathways. The beta-arrestin-mediated signaling is increasingly recognized as a key contributor to opioid-related adverse effects, particularly gastrointestinal motility suppression (leading to delayed gastric emptying, ileus, constipation, and PONV), respiratory depression, pruritus, and urinary retention. This mechanistic understanding has driven the development of biased opioid receptor agonists that preferentially activate G-protein signaling while minimizing beta-arrestin recruitment.

Trigonelline represents a novel class of biased mu-opioid receptor agonists designed to provide effective analgesia with an improved tolerability profile. Preclinical and early-phase clinical data suggest that trigonelline achieves comparable pain relief to conventional opioids while producing significantly fewer gastrointestinal side effects. Nevertheless, robust comparative data on trigonelline as monotherapy versus in combination with conventional opioids specifically for gynecologic laparoscopic postoperative analgesia are currently lacking. The present study addresses this evidence gap by directly comparing three analgesic regimens in a randomized controlled trial design.

Study Design This is a prospective, randomized, active-controlled, single-center, single-blind clinical trial conducted at the Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, China. The trial is investigator-initiated (IIT) and has been approved by the institutional Ethics Committee. The study is designed in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines.

A total of 165 participants will be enrolled and randomly allocated at a 1:1:1 ratio into three parallel arms, each receiving a distinct PCIA regimen for postoperative analgesia following gynecologic laparoscopic hysterectomy or myomectomy. No placebo arm is included; all participants receive an active analgesic regimen consistent with current standards of care.

Intervention Details

All study medications are prepared by the hospital pharmacy in identical 100-milliliter infusion bags connected to standardized PCIA pump devices. The external appearance, labeling (blinded), and pump programming parameters are uniform across all three arms:

Background infusion rate: 2 mL/hour Bolus dose: 0.5 mL Lockout interval: 15 minutes Maximum hourly limit: as per institutional protocol

Arm S receives sufentanil citrate injection at a total loading dose of 2.0 micrograms per kilogram (μg/kg) of body weight, diluted to 100 mL with 0.9% sodium chloride injection.

Arm O receives trigonelline injection at a total loading dose of 0.1 milligrams per kilogram (mg/kg) of body weight, diluted to 100 mL with 0.9% sodium chloride injection.

Arm Z receives a combination of sufentanil citrate at 1.0 μg/kg plus trigonelline at 0.05 mg/kg, diluted to 100 mL with 0.9% sodium chloride injection. This combination arm uses half the monotherapy dose of each agent, based on the hypothesis of synergistic or additive analgesic efficacy with potentially reduced dose-dependent adverse effects from either drug alone.

Randomization and Allocation Concealment Procedures The randomization sequence is generated prior to study initiation by an independent statistician who has no role in participant enrollment, intervention administration, or outcome assessment. A random number table method is employed for sequence generation. The completed randomization list is sealed and maintained solely by this third party.

When an eligible participant has completed screening and provided written informed consent, the enrolling research staff member communicates the sequential enrollment number to the third-party coordinator via a secure channel. The coordinator then reveals the corresponding group assignment. Study personnel involved in perioperative management and outcome assessment do not have access to the randomization list before or during the enrollment process. This procedure ensures allocation concealment and minimizes selection and allocation bias.

Blinding Methodology Given the practical constraints of perioperative anesthesia management - where the attending anesthesiologist must be aware of the assigned analgesic regimen for patient safety reasons - this study adopts a single-blind design in which the participant is blinded to group assignment.

To maintain the integrity of participant blinding, the following measures are implemented:

All PCIA pumps are externally identical in brand, model, size, and color Pump display screens are configured not to show drug names or concentrations All study medication solutions are colorless and transparent after dilution, making visual discrimination impossible Pump parameter settings (background rate, bolus volume, lockout time) are identical across all three arms Participants are informed during the consent process that the study compares different postoperative analgesic options without being told which specific regimen they will receive Research staff members who interact with participants during postoperative assessments are trained to avoid inadvertent unblinding through verbal or non-verbal cues

Perioperative Anesthesia Protocol (Standardized Across All Arms)

To ensure that any observed differences in outcomes can be attributed to the assigned PCIA regimen rather than variations in intraoperative management, all participants receive a standardized anesthesia protocol:

Preoperative preparation: Fasting for 8 hours and nothing by mouth for 4 hours prior to anesthesia induction. Peripheral intravenous access is established upon arrival in the operating room. Standard monitoring includes non-invasive arterial blood pressure, pulse oximetry (SpO2), electrocardiography (ECG), end-tidal carbon dioxide (EtCO2), heart rate, and body temperature.

Regional anesthesia adjunct: Prior to surgical incision, bilateral ultrasound-guided transversus abdominis plane (TAP) block is performed using 0.25% ropivacaine, 20 mL per side (total 40 mL), to provide abdominal wall analgesia and reduce intraoperative and early postoperative opioid requirements.

Anesthesia induction: Intravenous sequential administration of sufentanil (0.3 μg/kg), ciprofol (0.4 mg/kg), and cisatracurium (0.2 mg/kg). Tracheal intubation is performed using a video laryngoscope.

Mechanical ventilation: Tidal volume 6-10 mL/kg, respiratory rate 10-12 breaths/minute, inspired oxygen concentration 50-60%, with EtCO2 maintained between 35 and 45 mmHg.

Anesthesia maintenance: Continuous intravenous infusion of remimazolam (2-3 mg/kg/h), remifentanil (3-9 μg/kg/h), and cisatracurium (0.06-0.12 μg/kg/h), supplemented with sevoflurane inhalation at 1-2% end-tidal concentration. All agents are titrated dynamically according to hemodynamic responses and surgical stimulation. Cisatracurium infusion is discontinued approximately 30 minutes before anticipated end of surgery; other maintenance agents continue until skin closure.

Hemodynamic management: If mean arterial pressure decreases by more than 20% from baseline, or systolic blood pressure falls to 100 mmHg or below, or diastolic blood pressure falls to 60 mmHg or below, norepinephrine bitartrate is administered to maintain blood pressure within 20% of baseline values.

PCIA initiation: The assigned study analgesic pump is connected immediately upon completion of surgery, before emergence from general anesthesia.

Postoperative Management and Rescue Analgesia Protocol PACU phase: Participants are transferred to the Post-Anesthesia Care Unit (PACU) with the tracheal tube in place. Neostigmine and flumazenil are administered for neuromuscular reversal and sedation reversal as clinically indicated. Extubation is performed when the participant meets all of the following criteria: full return of consciousness, adequate spontaneous ventilation, ability to follow simple commands, and an Aldrete recovery score of 9 or higher. Participants are discharged from the PACU once stable.

Ward-based rescue analgesia: After returning to the general ward, if a participant reports a Visual Analog Scale (VAS) pain score of 4 or higher at rest, a single intravenous bolus of flurbiprofen axetil 50 mg is administered as rescue analgesia. A maximum of two rescue doses (total 100 mg) may be given within any 24-hour period. The timing, indication, dose, and response to each rescue analgesia event are documented in the case report form.

Management of PONV: If a participant experiences moderate to severe nausea or vomiting, intravenous ondansetron 5 mg is administered. Refractory cases may receive additional antiemetic therapy per institutional protocol.

Assessment Schedule and Data Collection Procedures

Trained research staff who are blinded to group assignment (to the extent feasible) will conduct postoperative assessments at five predetermined time points: 3 hours, 6 hours, 12 hours, 24 hours, and 48 hours after arrival in the PACU. At each assessment, the following data are collected:

VAS pain scores at rest and during coughing/movement (0 = no pain, 10 = worst imaginable pain) Ramsay Sedation Score (1 = anxious/agitated, 6 = unarousable) PCIA pump utilization data: total number of button presses, number of effective (delivered) presses Rescue analgesia: whether administered, number of doses, time of first rescue dose Adverse events: presence or absence and severity of nausea, vomiting, dizziness, somnolence, pruritus, chills, constipation, and abdominal distension Vital signs: SpO2, respiratory rate, heart rate, blood pressure

All data are recorded in real-time on standardized case report forms (CRFs). Safety Monitoring and Adverse Event Management Adverse events (AEs) are defined as any untoward medical occurrence in a participant after exposure to the study medication, regardless of causal relationship. Serious adverse events (SAEs) include events resulting in death, life-threatening conditions, hospitalization or prolonged hospitalization, persistent or significant disability, or congenital anomalies.

Predefined emergency management protocols are established for the following scenarios:

Respiratory depression / hypoxemia (SpO2 less than 92%, respiratory rate below 8 breaths/minute, or difficulty arousing): immediate cessation of PCIA background infusion, airway opening, high-flow oxygen supplementation, close monitoring; assisted ventilation with bag-valve-mask if no improvement; naloxone administration if indicated.

Excessive sedation (Ramsay score of 5-6): reduction or temporary discontinuation of background infusion; evaluation for contributing medications; manage per respiratory depression protocol if indicated.

Severe PONV: administration of ondansetron per protocol; intravenous fluid resuscitation; consideration of temporary PCIA adjustment for refractory cases.

Hypotension or bradycardia: identification of underlying cause (e.g., bleeding, residual anesthetic effect); fluid resuscitation; vasopressor or anticholinergic therapy as indicated.

Allergic reaction: mild reactions (rash, pruritus) are managed with antihistamines and PCIA discontinuation; severe reactions (bronchospasm, laryngeal edema, circulatory collapse) trigger immediate anaphylaxis resuscitation protocol with intravenous access establishment, fluid resuscitation, oxygenation, epinephrine, and SAE reporting within 24 hours.

Any SAE will be reported to the hospital Ethics Committee and the Clinical Research Management Committee within 24 hours of occurrence. An independent Data Safety Monitoring Board (DSMB) is not formally constituted for this IIT study given the low-risk nature of the interventions (all drugs are approved and used within labeled indications); however, the principal investigator and research team conduct regular internal safety reviews.

Quality Control and Data Integrity Source data verification is performed by the principal investigator or designated quality assurance personnel. CRF entries are cross-referenced against medical records, nursing charts, and PCIA pump logs at regular intervals. Any discrepancies are investigated and resolved with documentation. All protocol amendments require Ethics Committee approval before implementation.